Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes: A Systematic Review and Network Meta-analysis

It is interesting reading  ‘Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes: (1). I concur with  authors that comparisons for glycemic efficacy, safety and other outcomes are best demonstrated on administration in drug naive subjects. Comparative glycemic efficacy may be even better validated by expressing % decline rather than a point fall unless baseline HbA1c levels for individual agents are not significantly different and daily doses of agents are equivalent. Unfortunately, most comparative trials between newer and established drugs e.g. Metformin and Sulfonylureas have been conducted with maximum recommended daily doses of newer drugs with minimal to half the maximum daily doses of  older drugs (1, 2). These trials therefore are less than valid and unreliable. This observation is true for glycemic efficacy, safety as well as cardiovascular outcomes.

 Cardiovascular benefits noted in trials with newer drugs e.g. SGLT2 inhibitors, GLP 1 analogs may be attributed to improvement in glycemic control as documented in UKPDS since % decline in cardiovascular outcomes for 1 point fall in HbA1c was identical to that observed in UKPDS. e.g.  Decline of 20% in overall mortality and 14-16 % in myocardial infarctions (1, 3, 4). Fall in cardiovascular events with lowering of HbA1c is consistent with data showing increased  adverse cardiovascular outcomes with rising HbA1c  irrespective of the presence of diabetes. A recent report (5) documented  18 % increased occurrence of myocardial infarction for 1 point HbA1c rise over 6.5 %, almost identical to UKPDS (2). Moreover, none of these trials have examined ‘Legacy effect’ documented in UKPDS (1, 3, 4). Alternatively, some of these trials may have exaggerated the benefits (4). Finally, the validity and reliability of results from these trials sponsored and funded by pharmaceuticals should not be acceptable to regulating agencies e.g. FDA or practicing providers unless confirmed by independent entities similar to UKPDS (3).

Improvement in heart failure by SGLT2 Inhibitors can be attributed to glycosuria functioning as an osmotic diuretic (1, 4).  Thus it is likely that persistent hyperglycemia with resultant glycosuria inducing osmotic diuresis may prevent heart failure. However, glycosuria with its consequences, e.g.  genitourinary  bacterial and mycotic infections, Fournier’s gangrene, osteoporosis, ketoacidosis as well as several other serious and lethal side effects along with prohibitive costs of SGLT2 inhibitors (2) render them distinctly far less favorable when compared with older more effective, less expensive validated diuretics with proven long term record over several years.

References:

1. Apostolos Tsapas, Ioannis Avgerinos, Thomas Karagiannis, et al. Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes. A Systematic Review and Network Meta-analysis. Annals Internal Med. doe: 10.1177/1479164115570301. Pub 2015 Mar 15.

2. Kabadi UM. New Oral Diabetes Drugs are more effective than Older Agents: Real or a Fraud? Journal of Diabetes, Metabolic Disorders & Control (3), 3:1-4, 201

3. Kabadi, UM. United Kingdom Prospective Diabetes Study: A Different Perspective. Endocrine Practice. 8(1):61, 2002.

4. Kabadi UM. CARDIOVASCULAR OUTCOME TRIALS IN TYPE 2 DIABETES: RELIABLE OR BIASED! World Journal of Pharmaceutical and Medical Research, 3 (11): 33-35, 2017

5. de Jong M, Woodward M, Peters SAE.

Diabetes Care. 2020, 44: 2050-2059

Diabetes, Glycated Hemoglobin, and the Risk of Myocardial Infarction in Women and Men: A Prospective Cohort Study of the UK Biobank.

2020 Aug 3.

 doi: 10.1111/dom.14157. Online ahead of print.

We appreciate Dr Kabadi’s thoughts on the specifics of the research question of our systematic review and network meta-analysis (1), namely choice of clinically relevant subpopulations (drug naive patients), interventions (all approved doses of antidiabetic agents used in clinical practice) and outcomes (absolute rather than % change in HbA1c). These decisions were met a priori, to facilitate pragmatism and clinical relevance of our findings.

Even though it was beyond our scope to explore the association between intensive antihyperglycemic strategies and cardiovascular benefits, we do share concerns expressed regarding the complex relationship between glycemic control and cardiovascular endpoints. Notably, cardiovascular outcomes trials (CVOTs) were designed to assess only the pleiotropic effects of novel antidiabetic agents and eliminate the effect of glucose reduction on cardiovascular outcomes by aiming for glycemic equipoise, but mostly failed to achieve it. Hence, post-hoc analyses based on the findings of recent CVOTs suggest that the cardiovascular benefits of newer antidiabetic medications can be partly explained by a reduction of HbA1c, whereas follow-up reports of primary intensive glucose-lowering strategy trials have reached conflicting conclusions on this issue (2, 3, 4). On the other hand, it is unlikely that any favorable effects observed in CVOTs could be attributed to a legacy effect, given that, by definition, randomized controlled trials are designed to eliminate the effect of any known or unknown confounding factors, including past antidiabetic treatment.

It is true that the vast majority of clinical trials included in our review were funded by the pharmaceutical industry. We appreciate Dr Kabadi’s skepticism on this matter, underlining the need for enhanced involvement of academia in the design and conduct of clinical trials which could be facilitated by adopting a more pragmatic approach in future clinical research (5).

Finally, we assessed the effect of glucose-lowering medications, including SGLT2 inhibitors, on hospitalization for heart failure solely in patients with type 2 diabetes. As such, our study cannot reach any conclusions regarding the efficacy and safety of SGLT2 inhibitors as treatment options for heart failure. We agree that any clinical implications or policy decisions regarding the use of SGLT2 inhibitors in the treatment of patients with heart failure regardless of presence of type 2 diabetes should be based on a comprehensive evaluation of their overall efficacy and safety profile in combination with country-specific, methodologically robust cost-effectiveness studies.

References

1. Tsapas A, Avgerinos I, Karagiannis T, et al. Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes. Ann Intern Med 2020;173:278–86.
2. Holman RR, Paul SK, Bethel MA, et al. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–89.
3. Reaven PD, Emanuele N V., Wiitala WL, et al. Intensive glucose control in patients with type 2 diabetes - 15-year follow-up. N Engl J Med 2019;380:2215–24.
4. Fralick M, Colacci M, Odutayo A et al. Lowering of hemoglobin A1C and risk of cardiovascular outcomes and all-cause mortality, a meta-regression analysis. J Diabetes Complications. 2020 Nov;34(11):107704.
5. Bhandari M, Busse JW, Jackowski D, et al. Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. CMAJ 2004;170(4):477-80.